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  • Christianson, Helena CLund University,Lunds universitet,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,Lund Univ, Dept Clin Sci, Sect Oncol & Pathol, Lund, Sweden. (author)

Tumor antigen glycosaminoglycan modification regulates antibody-drug conjugate delivery and cytotoxicity

  • Article/chapterEnglish2017

Publisher, publication year, extent ...

  • 2017-04-07
  • IMPACT JOURNALS LLC,2017
  • electronicrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:uu-336048
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-336048URI
  • https://doi.org/10.18632/oncotarget.16921DOI
  • https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-140464URI
  • https://lup.lub.lu.se/record/cd230644-686b-418c-a811-66e9d48df0b2URI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • Aggressive cancers are characterized by hypoxia, which is a key driver of tumor development and treatment resistance. Proteins specifically expressed in the hypoxic tumor microenvironment thus represent interesting candidates for targeted drug delivery strategies. Carbonic anhydrase (CAIX) has been identified as an attractive treatment target as it is highly hypoxia specific and expressed at the cell-surface to promote cancer cell aggressiveness. Here, we find that cancer cell internalization of CAIX is negatively regulated by post-translational modification with chondroitin or heparan sulfate glycosaminoglycan chains. We show that perturbed glycosaminoglycan modification results in increased CAIX endocytosis. We hypothesized that perturbation of CAIX glycosaminoglycan conjugation may provide opportunities for enhanced drug delivery to hypoxic tumor cells. In support of this concept, pharmacological inhibition of glycosaminoglycan biosynthesis with xylosides significantly potentiated the internalization and cytotoxic activity of an antibody-drug conjugate (ADC) targeted at CAIX. Moreover, cells expressing glycosaminoglycan-deficient CAIX were significantly more sensitive to ADC treatment as compared with cells expressing wild-type CAIX. We find that inhibition of CAIX endocytosis is associated with an increased localization of glycosaminoglycan-conjugated CAIX in membrane lipid raft domains stabilized by caveolin-1 clusters. The association of CAIX with caveolin-1 was partially attenuated by acidosis, i.e. another important feature of malignant tumors. Accordingly, we found increased internalization of CAIX at acidic conditions. These findings provide first evidence that intracellular drug delivery at pathophysiological conditions of malignant tumors can be attenuated by tumor antigen glycosaminoglycan modification, which is of conceptual importance in the future development of targeted cancer treatments.

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Menard, Julien ALund University,Lunds universitet,Tumörmikromiljön,Forskargrupper vid Lunds universitet,Tumor microenvironment,Lund University Research Groups,Lund Univ, Dept Clin Sci, Sect Oncol & Pathol, Lund, Sweden.(Swepub:lu)med-jlm (author)
  • Chandran, Vineesh IndiraLund University,Lunds universitet,Tumörmikromiljön,Forskargrupper vid Lunds universitet,Tumor microenvironment,Lund University Research Groups,Lund Univ, Dept Clin Sci, Sect Oncol & Pathol, Lund, Sweden.(Swepub:lu)med-vcn (author)
  • Bourseau-Guilmain, ErikaMontpellier Univ, CNRS, UMR 5237, CRBM, Montpellier, France.,CNRS UMR 5237 CRBM, Montpellier University, Montpellier, France,University of Montpellier(Swepub:lu)med-ebi (author)
  • Shevela, DmitryUmeå University,Umeå universitet,Kemiska institutionen,Umea Univ, Chem Biol Ctr, Dept Chem, Umea, Sweden.(Swepub:umu)dmsh0004 (author)
  • Lidfeldt, JonLund University,Lunds universitet,Tumörmikromiljön,Forskargrupper vid Lunds universitet,Tumor microenvironment,Lund University Research Groups,Lund Univ, Dept Clin Sci, Sect Oncol & Pathol, Lund, Sweden.(Swepub:lu)med-jlt (author)
  • Månsson, Ann-SofieLund University,Lunds universitet,Tumörmikromiljön,Forskargrupper vid Lunds universitet,Tumor microenvironment,Lund University Research Groups,Lund Univ, Dept Clin Sci, Sect Oncol & Pathol, Lund, Sweden.(Swepub:lu)mikr-ama (author)
  • Pastorekova, SilviaSlovak Acad Sci, Inst Virol, Biomed Res Ctr, Bratislava, Slovakia.,Biomedical Research Centre, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia (author)
  • Messinger, JohannesUppsala University,Umeå University,Umeå universitet,Uppsala universitet,Molekylär biomimetik,Umea Univ, Chem Biol Ctr, Dept Chem, Umea, Sweden,Kemiska institutionen,Department of Chemistry – Ångström, Molecular Biomimetics, Uppsala University, Uppsala, Sweden(Swepub:umu)jome0007 (author)
  • Belting, MattiasLund University,Lunds universitet,Tumörmikromiljön,Forskargrupper vid Lunds universitet,Tumor microenvironment,Lund University Research Groups,Skåne University Hospital,Lund Univ, Dept Clin Sci, Sect Oncol & Pathol, Lund, Sweden.;Skane Univ Hosp, Dept Oncol, Lund, Sweden.(Swepub:lu)medk-mbe (author)
  • TumörmikromiljöSektion I (creator_code:org_t)

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  • In:Oncotarget: IMPACT JOURNALS LLC8:40, s. 66960-669741949-2553

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